Sunday, June 6, 2010

Biogen sells AVONEX, an interferon-beta product used in the treatment of multiple sclerosis. On May 27, Biogen filed a patent infringement lawsuit against Pfizer, Serono, Bayer (formerly known as Berlex) and Novartis for the production and sale of the competing interferon-beta products REBIF, BETASERON and EXTAVIA

Biogen's patent, which issued in 2009 and is not due to expire until at least 2026, claims priority to a British patent application filed in 1980. This is a classic example of what many would refer to as a "submarine patent”: not only does the term of the patent extend nearly 50 years after the original filing date, but the patent application was not published prior to issuance of the patent in 2009, and thus the public had no notice that this potentially blockbuster patent was pending in the US patent office.

In this article, I briefly explore the history of the asserted patent, the history of patent litigation involving the marketing of interferon-beta as a protein therapeutic, and some potentially winning arguments the defendants could raise in their defense.

History of a Biotech Submarine Patent

A submarine patent is an informal term used to describe patents which issue without warning many years after the original filing date of the application. Wikipedia has a page devoted to submarine patents, which explains that they typically arise out of two unique aspects of US patent law: (1) a 17 year term that does not start running until the date the patent is issued (only for patents arising out of an application filed prior to June 8, 1995); and (2) the secret status of patent applications that have not been published.

Prior to November 29, 2000, US patent applications were not published unless and until the application resulted in an issued patent. Even today, an applicant for US patent can choose not to allow the PTO to publish its application so long as the applicant does not seek patent protection outside the US. Without publication, the public has no notice that the application is pending in the patent office, and thus no warning prior to the issuance of the resulting patent. Some have proposed amending US patent law to require publication of all patent applications 18 months after filing, but as of yet this is just a proposal.

Submarine patents are also fostered by relatively loose continuation rules in the US, which permit an applicant to keep a patent application pending virtually indefinitely, and to freely amend the claims to encompass previously unclaimed subject matter (so long as the later claimed subject matter is adequately disclosed in the application as filed). In a previous post, I discussed the relationship between continuation practice and late claiming, and my suspicion that restrictions on continuation practice proposed by the patent office a couple years ago were largely intended to address perceived abuses of continuation practice.

A few years ago, Mark Lemley (Stanford law professor) and Kimberly Moore (currently a judge on the Federal Circuit, but at the time a law professor) wrote a law review article complaining that some patent applicants, particularly pharmaceutical companies, were abusing continuation practice to extend patent protection beyond the statutory term, a practice they refer to as "evergreening." They would likely point to Biogen's patent as an example of what they consider to be abusive continuation practice.

Biogen’s patent, US patent number 7,588,755, arose out of a patent application filed by Walter Fiers in April of 1981 (and claiming priority to a British application filed in April of 1980), which disclosed, among other things, the DNA sequence for the gene encoding interferon-beta, methods of using the gene to produce recombinant interferon-beta protein, and use of the interferon beta protein as a biologic drug for the treatment of cancer and viral conditions. The core claims, directed to the gene itself, became involved in a three-way patent interference, which eventually went before the Federal Circuit and in 1993 resulted in Fiers v. Revel, a seminal biotech patent decision that proved instrumental in the creation of what is often referred to as the "Lilly written description requirement" (the subject of the recent Ariad v. Lilly decision).

In Fiers v. Revel, the Federal Circuit affirmed the board's decision in favor of Sugano, the Japanese party to the interference, and thus denying Fiers a patent on the gene itself. Sugano’s patent on claiming the gene (5,326,859) issued on July 5, 1994, and assuming no patent term extension should expire July 5, 2011, more than 30 years after the patent application was initially filed. In this case, the long pendency between filing date and patent issuance can largely be attributed to the time consumed by the interference proceeding. According to USPTO records, Sugano’s patent is assigned to the Japanese Foundation for Cancer Research, and has never been asserted in a lawsuit.

Although Fiers lost the battle, he did not necessarily lose the war. Denied patent coverage of the gene itself, he took advantage of continuation practice and on May 25, 1995, filed a divisional application claiming priority to the 1980 British patent application. Note that the application was filed just in time to still qualify for a 17 year from date of issuance term; if the application had been filed a few weeks later it would have been subject to a 20 year term from the date the original application was filed, and thus no patent could have issued having a term extending beyond 2001.

The patent ultimately issued on September 15, 2009, with claims essentially reciting methods of using recombinantly produced interferon-beta for “immunomodulation or treating a viral conditions, a viral disease, cancers or tumors." Because the divisional application was filed prior to June 8, 1995, it was granted a 17 year term starting on the date of issuance, resulting in a patent term (assuming no extensions) that will not expire until September 15, 2026, more than 46 years after the patent application was initially filed in Great Britain.

It bears emphasizing that this sort of long delay between filing date and patent expiration is only possible for patent applications filed prior to June 8, 1995. But this case illustrates that some of these applications are still pending, and in cases where the application has not been published there is no public notice of the potential landmine that might explode for companies like Bayer and Novartis at any time.

Note that in some ways the method of treatment patent obtained by Biogen is potentially more valuable than Sugano’s gene patent. The gene patent could be circumvented by producing the interferon-beta product outside of the US, and then importing it into the US. Use of the gene outside of the US, and importation of the protein product, would not infringe a patent limited to the gene itself. In contrast, Fiers method of treatment patent could be infringed by a company selling interferon-beta in the US, regardless of where it is produced.

Furthermore, because of the long delay between the interference and the issuance of Fiers’ method of treatment patent, the term of the patent extends 15 years beyond the term of Sugano’s gene patent. Assuming that the market for interferon-beta as a therapeutic has expanded over time, the 17 years covered by Fiers’ patent is more valuable than Sugano’s 17 year term.

As an aside, note also that Sugano’s gene patent is invalid according to the holding of a recent district court decision in the ACLU challenge to Myriad’s BRCA gene patents, although I feel fairly confident that that decision will not stand (as discussed here).

Previous interferon-beta patent litigation

This is not the first patent infringement lawsuit between these parties involving interferon-beta. On July 3, 1996, Biogen filed a declaratory judgment action against Bayer (at that time Berlex) seeking a declaration that Berlex patents claiming methods for the recombinant production of interferon in Chinese hamster ovary (CHO) cells were not infringed by Biogen's method of producing its interferon-beta product (AVONEX). A district court granted summary judgment in Biogen's favor, finding no infringement.

While the case was on appeal to the Federal Circuit, the parties entered a settlement agreement allowing Biogen to stay on the market, pursuant to which Biogen agreed to pay Berlex $20 million upfront and an additional $55 million if the Federal Circuit reversed the district court’s ruling granting summary judgment in Biogen’s favor (the litigation and settlement are discussed in my article on human gene patent litigation, available here). Ultimately, the Federal Circuit affirmed the lower court's decision that Biogen did not literally infringe Berlex’s patents, but remanded the case to the district court to determine whether there was infringement under the doctrine of equivalents (Biogen v. Berlex, 318 F.3d 1132 (Fed. Cir. 2003)). However, as a result of the settlement the district court never had to decide the issue of eivalent infringement.

Potential Weaknesses in Biogen’s Case

I can imagine a couple of potential avenues by which the defendants in this case might escape liability for infringement of Biogen’s patent. For one thing, the primary use of interferon-beta products is in the treatment of multiple sclerosis. But the only independent claim in the patent recites a "method for immunomodulation or treating a viral conditions, a viral disease, cancers or tumors comprising the step of administering to the patient in need of such treatment a therapeutically effective amount of a composition comprising [recombinantly expressed interferon-beta].” A court would likely only find this claim infringed by use of interferon-beta in the immunomodulation or treatment of "viral conditions, viral diseases, cancers or tumors."

Clearly, MS is not a tumor or cancer, and to my knowledge it has not been established that it is caused by a virus. For example, an article on the website WebMD entitled Multiple Sclerosis: What Causes It? States that “[d]octors still don't understand what causes MS, but there are interesting data that suggest that genetics, a person's environment, and possibly even a virus may play a role.” The patent owner bears the legal burden of proving infringement, and without some fairly persuasive evidence showing that MS is a viral disease, I think that Biogen might have difficulty proving infringement.

There is also the issue of prosecution latches. In Symbol Technologies v. Lemelson, the Federal Circuit affirmed a lower court's determination that certain patents were unenforceable for unreasonable delays in the prosecution of the patent. In that case, the lag between filing date and patent issuance for the patents in suit ranged from 18 to 39 years.

Earlier this year, in Cancer Research Technology v. Barr Laboratories, Inc., 679 F.Supp.2d 560 (D.Del.,2010), a district court cited Symbol Technologies in ruling that a drug patent was unenforceable based on nine years of delay in prosecution.

In this case, Biogen’s patent issued about 28 years after the initial 1981 US filing date. The patent interference was limited to claims directed towards the gene itself, not claims to the method of treatment which ultimately issued in the patent, so I don't think Biogen will be able to point to the interference as an excuse for the 28 year delay. In any event, I think it is likely Biogen will need to provide some justification for the long delay or risk having its patent ruled unenforceable.

About Me

I am a law professor at the University of Missouri-Kansas City School of Law. My primary research interests lie at the intersection of biotechnology and intellectual property. This blog provides analysis and commentary on recent developments relevant to this area of the law.